1-substituted-5-nitroimidazol-2-ylalkyl-(n-substituted)-carbamates

ABSTRACT

1-SUBSTITUTED-5-NITROIMIDAZOL-2-YLALKYL CARBAMATES, CONTAINING N-HYDROXY, N-ALKOXYALKYL, OR N-HYDROXYALKYL SUBSTITUTION, OR THE ANALOGOUS THIOL SUBSTITUTION, AND ACID ADDITION SALTS THEREOF ARE PREPARED FROM 1-SUBSTITUTED-5-NITROIMIDAZOLES HAVING AT THE 2-POSITION OF THE IMIDAZOLE RING AN HYDROXYALKYL, MERCAPTOALKYL, HALOALKYL, HALOCARBONYLALKYL, OR HALOTHIOCARBONYLOXYALKYL RADICAL. THE 1SUBSTITUTED-5-NITROIMIDAZOL - 2 - YLALKYL-(N-SUBSTITUTED)CARBAMATES ARE USEFUL IN THE TREATMENT OF PARASITIC DISEASES. ANTIPARASITIC COMPOSITIONS IN WHICH THE ACTIVE INGREDIENT IS A 1 - SUBSTITUTED-IMIDAZOL-2-YLALKYL-(N-SUBSTITUTED)-CARBAMATE ARE ALSO PROVIDED.

a m 781 *1-SUBSTITUTED-S-NI'IROIMIDAZOL-Z-YLALKYL(N-SUBSTITUTED)-CARBAMATES John A. Carlson, Nassau, N.Y., Dale R. Holf,Basking 5 Ridge, NJ., and Clarence S. Rooney, Beaconsfield,Queb1e?,JCanada, assiguors to Merck & Co., Inc., Rahway,

No Drawing. Application Sept. 5, 1969, Ser. No. 855,765,

now Patent No. 3,646,027, which is a continuation-inpart of applicationSer. No. 550,932, May 18, 1966, which in turn is a continuation-impartof application Ser. No. 470,239, July 7, 1965, both now abandoned.Divided and this application Nov. 12, 1971, Ser. No.

rm. Cl. C07d 49/36 US. Cl. 260-309 14 Claims ABSTRACT OF THE DISCLOSURE1-substituted-5-nitroimidazol-2-ylalkyl carbamates, containingN-hydroxy, N-alkoxyalkyl, or N-hydroxyalkyl substitution, or theanalogous thiol substitution, and acid addition salts thereof areprepared from l-substituted-S-nitroimidazoles having at the 2-positionof the imidazole ring an hydroxyalkyl, mercaptoalkyl, haloalkyl,halocarbonylalkyl, or halothiocarbonyloxyalkyl radical. The 1-substituted-S-nitroimidazol 2 ylalkyl-(N-substituted)- carbamates areuseful in the treatment of parasitic diseases. Antiparasiticcompositions in which the active ingredient is a 1substituted-imidazol-Z-ylalkyl-(N-substituted)-carbamate are alsoprovided.

CROSS REFERENCE TO RELATED APPLICATIONS This appliction is a divisionalapplication of our c0- pending application, U.S. Ser. No. 855,765 filedSept. 5, 1969, now US. Pat. 3,646,027 which in turn was acontinuation-in-part appliction of copending US. Ser. No. 550,932 filedMay 18, 1966, now abandoned, which in turn, was a continuation-in-partapplication of US. Ser. No. 470,239 filed July 7, 1965 and nowabandoned.

DESCRIPTION OF THE PREFERRED EMBODIMENTS This invention relates to newchemical compounds. More particularly, it relates to novel imidazolecarbamates. It is concerned further with chemical synthesis of suchsubstances and with novel imidazole compounds useful as intermediates insuch synthesis. In addition, it is concerned with antiparasiticcompositions containing the imidazole carbamates of this invention asactive ingredients.

One object of this invention is to provide new and useful1-substituted-imidazol-Z-ylalkyl, N-substituted carbamates and acidaddition salts thereof. It is also an object to provide1-substituted-5-nitroimidazol-2-ylalkyl-(N-substituted)-carbamates whichhave antiparasitic activity. Another object is to provide methods formaking these compounds from 1-substituted-S-nitroimidazoles having atthe 2-position of the imidazole ring, a hydroxyalkyl, mercaptoalkyl,haloalkyl, halocarbonyloxyalkyl, or halothiocarbonyloxyalkyl radical.

A further object is to provide compositions useful against parasiticdisease, for example, trichomoniasis, enterohepatitis and asantihelminthic compositions against ascarids and schistosomes. Certainof them are also effective against amoebiasis and trypanosomiasis aswell as chronic respiratory diseases in fowl and swine caused by PPLOorganisms. Certain of the compositions of the pits ent invention alsoshow antibacterial activity. In these compositions,1-substituted-S-nitroimidazol-Z-ylalky1-(N- substituted)-carbamates arepresent as active ingredients.

The novel imidazole carbamates of this invention may be represented bythe following structural formulae:

in which R, is loweralkyl having 1-5 carbon atoms; Q is loweralkylene orloweralkylidene having 1-4 carbon atoms; A and M are each oxygen orsulfur; R is hydrogen or loweralkyl having 1-3 carbon atoms; and R ishydroxy, hydroxyloweralkyl, loweralkoxyloweralkyl, thiol,thio-loweralkyl, or the loweralkylthioloweralkyl, the loweralkyl in Rhaving the meaning 1-4 carbon atoms.

Also within the purview of the invention are acid addition salts ofthese imidazole carbamates. The salt may be of an inorganic acid such asthe hydrochloride, hydrobromide, phosphate, nitrate or sulfate, or of anorganic acid, examples of which are the citrate, tartrate, adipate,methanesulfonate, p-toluenesulfonate and the like. Nontoxic acidaddition salts, i.e., those tolerated by the host at the dose levelsemployed, are employed when the carbamates are to be used in their saltform as antiparasitic agents.

The preferred compounds of this invention are the 1-substituted-S-nitroimidazol-Z-ylalkyl-(N-hydroxy and N-hydroxyloweralkyl)-carbamates. More specifically, the preferredcompounds are the imidazolylalkyl carbamates of the invention as shownin Formula I supra, wherein Q is loweralkylene suitably methylene orethylene, or loweralkylidene suitably l-ethylidene, R is alkyl such asmethyl or ethyl, and the sub-group THE GENERAL PROCESSES (i) Theimidazole halocarbonate process One process for making the carbamates ofthis invention consists in reaction of the halocarbonate orhalothioncarbonate ester of 1-substituted-Z-hydroxyalkyl-(or 2-mercaptoalkyl)-5-nitroimidazole with aprimary or secondary amine. Thereaction may be schematically represented as follows:

The two reactants are contacted in a suitable inert solvent medium suchas dioxane, tetrahydrofuran or an aromatic hydrocarbon, such as benzene,at a temperature in the range of about -75 C. An excess of aminereactant is generally employed and good results are obtained with fromabout 2.0-5.0 moles of amine per mole of halocarbonate ester, such aschlorocarbonate ester, at reaction temperatures of from about -40 C. formost amines. It might be noted that the ester reactants are frequentlyreferred to by those in this art as the haloformate (orhalothionformate) esters of the l-substituted-Z-hydroxyalkyl (ormercaptoalkyl)-5-nitroimidazole.

The molar excess of amine is desired since it is convenient andcustomary to use 1 mole of the amine (in addition to the mole needed forthe reaction itself) as an acid binding agent to neutralize the acidformed in the reaction. The haloformate ester starting material may becharged to the reaction in the form of an acid addition salt, and it isthen necessary to have another mole of amine to neutralize this salt.

Amines which are suitable for use in this reaction include ethanolamine,propanolamino, ethoxyethylamine, ethoxypropylamine, and hydroxylamine.

(ii) Preparation of imidazole halocarbonate of the stnucture -I|N 0 NiJ- AH a N [Q] fir where Q, A, and R are as above. Generally the lowertemperatures are used with phosgene, and higher temperatures withthiophosgene. The process is conducted in an inert organic solventmedium. Satisfactory solvents are dioxane, tetrahydrofuran and toluene,or mixtures thereof, as well as ketones and esters such as ethylacerate. It is desirable to employ a solvent in which the imidazolereactant is essentially completely soluble. For best results, theprocess is conducted in the presence of an acid binding agent, normallya tertiary amine such as trialkylamine or dimethylaniline, althoughsolvents such as tetrahydrofuran and dioxane may themselves be used asacid binding agents in this reaction. The chloroformate orchlorothionformate ester may be isolated, if desired, but this isunnecessary, and it is a preferred embodiment of the invention toprepare the ester in solution and to react it without isolation with theamine.

(iii) The phenyl halocarbonate method- Still another process which isvery useful for preparing the novel imidazolylalkyl carbamates describedherein comprises the conversion of a l-substituted-Z-hydroxyalkyl (ormercaptoalkyl) imidazole to a phenyl carbonate or phenyl thioncarbonatederivative, and subsequent treat- '4 ment of said carbonate orthioncarbonate with an amin as illustrated below:

wherein Q, R R R A and M are as above and X is halo.

This process for making imidazolylalkyl carbamates, which process isitself not a part of this invention, but is rather an invention of ourcolleague George Gal, is highly satisfactory for obtaining carbamates.This process is described more fully in US. Pat. 3,458,528, issued July29, 1969.

In the preferred modification of this process, the significance of thesubstituents is as follows:

Q is loweralkylene suitably methylene or ethylene; or

loweralkylidene suitably l-ethylidene;

R is loweralkyl suitably methyl, ethyl or propyl;

A and M each represent oxygen or sulfur;

R is hydrogen or loweralkyl and R is alkyl, hydroxyalkyl, suitablyhydroxyloweralkyl, such as hydroxyethyl; alkoxyalkyl, such asethoxyethyl or ethoxypropyl; or hydroxy.

In carrying out this process, a l-loweralkyl-Z-hydroxyalkyl (ormercaptoalkyl)-5-nitroimidazole such as 1- methyl-Z-hydroxyalkyl (ormercaptoalkyl)-5-nitroimidazole such as is first reacted for examplewith phenoxy carbonyl chloride (phenyl chloroformate) orphenoxythiocarbonyl chloride (phenyl thionchloroformate). This reactionis conveniently brought about in an organic solvent, such as pyridine,one of the picolines, or lutidine. These bases, in addition to servingas the liquid solvent medium, also serve to bind the acid formed duringthe reaction. Alternatively, a non-basic solvent for the reactants suchas dioxane or chloroform may be employed, and sufficient tertiary amineor alkali metal hydroxide added to bind the liberated hydrogen chloride.It is preferred to employ a slight molar excess of phenyl chloroformatereactant and to carry out the process at temperatures of from about 5 C.to about 45 C. Preferably, the reactants are mixed at about 0 C. and thereaction then continued at about room temperature for the desired time.When a phenyl carbonate of a 2-hydroxymethyl or Z-mercaptomethyl isbeing prepared, reaction times of from about 1-5 hours are satisfactoryfor good results. However, longer times of up to about 30 hours may benecessary for complete reaction in the case of Z-(a-hydroxyethyl) andZ-(a-mercaptoethyl)imidazoles. The resulting imidazole phenyl carbonate,such as for instance 1-methyl-5-nitroimidazol-2-ylmethyl phenylcarbonate or l-methyl-S-nitroirnidazol-2-ylmethyl phenyl thioncarbonateis conveniently recovered by quenching the reaction mixture in icewater, thus precipitating the desired product.

These substances may be used without further purification in the nextstep of the process, and this is preferred in the case of the phenylthioncarbonates which are less stable than the phenyl carbonates.

The imidazolylalkyl carbamate is then obtained by intimately contactingthe imidazole phenyl carbonate or phenyl thioncarbonate with an amine inan inert organic solvent medium. For this purpose, chloroform or etherssuch as dioxane, tetrahydrofuran or ethylene glycol dimethyl ether aresatisfactory. It will, of course, be understood that the particularcarbamate produced will depend upon the amine reactant used. Thereaction is a rapid one and is normally substantially complete in about1-5 hours. The imidazole phenyl carbonate and the amine may be reactedin essentially equimolar amounts although it is preferred to employ anexcess of the amine. Good results are obtained by using from 1.0-4 molesof amine per mole of phenyl carbonate.

THE SPECIFIC PROCESSES The following processes are directed to thepreparation of carbamates having particular substituents attached to thenitrogen of the carbamate group. Although these processes are directedto the formation of the compounds having these particular substituents,it should be understood that they are not specifically limited thereto.

(i) 5-nitroimidazol-Z-ylalkyl N-hydroxymethylcarbamateS-nitroimidazol-Z-ylalkyl N-hydroxymethylcarbamates may be obtained byreacting the corresponding S-nitroimidazol-Z-ylalkyl carbamate withformaldehyde. In the preferred modification of the process, the5-nitroimidazole carbamate, suitably a 1-R-S-nitroimidazol-Z-ylmethylcarbamate, wherein R is as defined above, isdissolved in an inert solvent, dimethyl sulfoxide being particularlysuitable, and heated in a sealed vessel with an excess ofparaformaldehyde, 2 moles excess being preferred, at from 70-150 C. forfrom 18 to 30 hours. In one method of isolation, the solvent isevaporated from the reaction mixture, the residue dissolved in asuitable water miscible solvent, such as, dimethylformarnide and wateradded. The product separates as a crystalline precipitate and may beisolated by filtration.

Included among the compounds which may be produced in accordance withthis procedure are:

1-methyl-S-nitroimidazol-Z-ylmethyl N-hydroxymethylcarbamate;

1-(l'-methyl-5-nitroimidazol-2'-ylethyl) N-hydroxymethylcarbamate;

2-( l-methyl-5'-nitroimidazol-2'-yl)ethyl N-hydroxymethylcarbamate; and

l-ethyl-S-nitroimidazol-2-yl-methyl N-hydroxymethylcarbamate.

(ii) S-nitroimidazol-Z-ylalkyl N-alkoxyalkylcarbamates S-nitroimidazol 2ylalkyl N alkoxyalkylcarbamates may be produced by reacting thecorresponding S-nitroimidazol-Z-ylalkyl N-hydroxyalkyl carbamate with analkanol in the presence of an acid. In the preferred procedure, theN-hydroxymethylcarbamate, suitably a 1-R -5- nitroimidazol-2-ylmethyl-Nhydroxycarbamate, wherein R is as defined above, for example,1-methyl-5-nitroimidazol-Z-ylmethyl N-hydroxymethylcarbamate, is mixedwith the alkanol, for example, ethanol or methanol in the presence of acatalytic amount of strong acid, hydrochloric acid or p-toluene sulfonicacid being preferred, and allowed to stir for 12 to 24 hours, at between15 C. and 30 C. The product may be isolated by extraction of thereaction mixture with a suitable solvent such as, chloroform and workingup in the usual manner.

Included among the products which may be obtained by means of thisprocedure are:

1-methyl-5-nitroimidazol-Z-ylmethyl N-ethoxymethylcarbamate;

1-methyl-5nitroimidazol-Z-ylmethyl N-propoxymethylcarbamate;

1-( 1'-methy1-5'-nitroimidazol-2'-yl) ethyl N-methoxymethylcarbamate;and

1-ethyl-5-nitroimidazol-2-ylmethyl N-ethoxymethylcarbamate.

The 1-substituted-Z-imidazolylalkyl (N substituted)- carbamates abovehave antiprotozoal activity, and are particularly active against thecausative organisms of the protozoal parasitic diseases trichomoniasisand enterohepatitis. Certain of them are also effective againstamoebiasis and trypanosomiasis, as well as against the PPLO organismsand schistosomes. It will, of course, be understood that the compoundsdiffer in their degree of efficiacy against these various organisms.

Trichomoniasis is a protozoan disease caused by parasites of the genusTrichomonas. The compounds of the invention are effective against theparticularly troublesome form of trichomoniasis known as T. vaginalisvaginitis, caused by infestation of the vagina with T. vaginalis. Intreating this disease, the the imidazolylalkyl carbamates may beadministered either orally or topically. For oral administration unitdosage, forms such as tablets or capsules are normally employed whichmay contain from about 50 to about 500 mg. of active ingredient. Theseare prepared by techniques known in the art, and contain the usualdiluents, granulating agents, extenders and/or lubricating agents knownto be satisfactory for the compounding of tablets and capsules. It ispreferred to administer the compounds of the invention orally at a doselevel of from about 254,000 mg./day, in either single or divided doseswith divided doses being used more frequently than a single daily dose.An example of a suitable compressed tablet is the following:

If desired, tablets may be sugar coated or enteric coated by standardtechniques. Alternatively, the anti-trichomonal agent may be formulatedin capsule form using fillers such as lactose, starch or kaolin. Atypical capsule would contain 250 mg. of, for instance,l-methyl-S-nitroimidazol-Z-ylmethyl N-hydroxy carbamate, 2-3 g. ofmagnesium stearate and about 75 mg. of lactose in a No. 0 size capsule.Tablets and capsules containing smaller quantities of active ingredientmay be made by reducing proportionately the amounts of excipients anddiluent illustrated above. Alternatively, the carbamates may beadministered orally in liquid pharmaceutical vehicles such as solutions,emulsions, syrups or suspensions containing the diluents, flavoringagents and preservatives customarily employed in the pharmaceutical art.

For topical application, vaginal creams or suppositories containing theactive ingredient may be used. To illustrate, a cream is prepared bymixing sulficient quantities of hydrophilic ointment and Water,containing from about meleagridis. It is also known as turkey blackheaddisease.

The imidazolylalkyl carbamates of this invention are useful in theprevention and treatment of this disease and for this purpose areadministered to turkeys mixed with an element of turkey sustenance, i.e.in the feed or drinking water. Although the optimum dose level willdepend on the particular compound employed and the severity of theinfection, good control of enterohepatitis is obtained by orallyadministering to the turkeys a feed containing.

from about 0.003% to about 0.1% by weight of carbamate. When thematerial is administered via the drinking water, somewhat higher levelsmay be employed, especially for therapeutic use. For instance, thedrinking water may contain up to about 0.2% by weight of the activeingredient with good results. Those substances previously mentioned aspreferred anti-trichomonal agents are also among those preferred incombating turkey blackhead.

As previously stated, the imidazolyalkyl carbamate described herein mayalso be employed against trypanosomiasis and amoebiasis. In addition,certain of them, and particularly 1-methyl-5-nitroimidazol-2-ylmethyl N-hydroxycarbamate posses activity against the pleuro-pneumonia likeorganisms which have come to be known as PPLO organisms.

The imidazolylalkyl carbamates are efltective against PPLO organismswhen the compound is administered to fowl or swine in feed containingfrom about 0.003% to about 0.1% by weight of carbamate. The preferreddosage level, however, is between from about 0.003% to 0.08% by weight.

The following examples are given for the purpose of illustration and notby way of limitation.

In addition, preparation of the starting materials can be found in US.Pat. 3,458,528 or Belgium Pat. 683,796 issued I an. 9, 1967, anequivalent of the disclosure in US. Ser. No. 550,932 filed May 18, 1966,a parent application of the instant application.

EXAMPLE 1 1-methyl-5-nitroimidazol-Z-yl-methyl chloroformate 3.12 g,1-methyl-2-hydroxymethy1-S-nitroimidazole is dissolved in a mixture of4.3 ml. of dimethylaniline and 20 ml. of dioxane. This solution is thenadded dropwise to 30 ml. of phosgene. The resulting suspension isstirred for two hours at 5 C., and then for two hours at roomtemperature. The solvent is then removed by blowing dry nitrogen throughthe suspension for two hours. The oil remaining at the end of this timeconsists predominantly of l-methyl-S-nitroimidazol-Z-ylmethylchloroformate.

In accordance with the above procedure, but starting withl-methyl-Z-mercaptomethyl nitroimidazole, in place ofl-methyl-Z-hydroxymethyl 5 nitroimidazole,

'there is obtained 1-methyl-5-nitroimidazol-2-yl-methylchlorothioformate.

In accordance with the above procedure, but starting with either of theaforementioned nitroimidazoles but using thiophosgene in place ofphosgene, there is obtained 1-methyl-5-nitroimidazol-2-yl-methylchlorothionformate and 1-methyl-S-nitroimidazol-Z-yl-niethylchlorodithioformate.

EXAMPLE 2 1-methyl-5-nitroimidazol-2-ylmethyl carbamate 0.05 g. ofl-methyl-S-nitroimidazol-Z-ylmethyl phenyl carbonate is dissolved slowlyin 50 m1. of liquid ammonia. After solution is complete, the ammonia ispermitted to evaporate and the residue washed with ethanol andrecrystallized from methanol to yieldl-methyl-S-nitroimidazol-Z-ylmethyl carbamate; M.P. 166170 C.

In accordance with the above procedure, but starting withl-(l-methyl-S-nitroimidazolo-Z-yl)-ethyl phenyl carbonate,2-(l-methyl-5-nitroimidazol-2-yl)-ethyl phenyl carbonate and3-(1-methyl-5-nitroimidazol-Z-yl)-p-rop-2- en-l-yl phenyl carbonate inplace of l-methyl-S-nitroimidazol-2-y1-methyl phenyl carbonate there isobtained the corresponding l-(1-methyl-5-nitr0imidaz0l-2-yl)ethylcarbamate, 2-(1-methyl-5-nitroimidazol-2-y1)ethyl carbamate, and3-(l-methyl-S-nitroimidazol-Z-yl)prop-2-eny1 carbamate.

EXAMPLE 3 1-methyl-5-nitroimidazol-2-ylmethylcarbamate 3.12 g. of1-methyl-2-hydroxymethyl-S-nitroimidazole is dissolved in 100 ml. ofmethylene dichloride and cooled to "0 C. 2.64 g. of sodium cyanate and4.5 g. of trifluoroacetic acid are added. The flask is stoppered tightlyand the mixture stirred for 24 hours at 0 C. 200 ml. of methylenechloride is then added and the mixture washed with saturated aqueouspotassium bicarbonate solution. The methylene chloride solution isconcentrated to dryness in vacuo to give a residue ofLmethyl-5-nitro-2-imidazolylmethyl carbamate. This solid isrecrystallized from a minimum volume of ethyl acetate to givesubstantially pure 1- methyl-5-nitroimidazol-2-ylmethyl carbamate; M.P.166- 170 C.

EXAMPLE 4 1-methyl-S-nitroimidazol-Z-ylmethyl thiolcarbamate 1.35 g. ofl-methyl-2-chloromethyl-5-nitroimidazole is dissolved in 25 m1. of dryethanol at room temperature, and 1.11 g. of potassium thiocyanate isadded to this solu tion. The resulting mixture is refluxed for two hoursand then allowed to stand at room temperature for about 12 hours. It iswarmed to about 75 C. on a steam bath and the solid material removed byvfiltration. The filtrate is diluted with an equal volume of water andthe resulting solution chilled and scratched to induce crystallization.The solid which forms is removed by filtration, washed with ice-waterand dried. It is 1-methyl-2-thiocyanomethyl-5-nitroimidazole; M.P.87-88" C. This product is crystallized from a minimum volume of benzenecontaining a trace of hexane to give yellow crystals of 1-methyI-Z-thiocyanomethyl-S-nitroimidazole; M.P. 87.5- 88 C.

5 g. of 1-methy1-2-thiocyanomethyl-S-nitroimidazole is added portionwiseover a period of 15 minutes to 25 ml. of cold concentrated sulfuricacid. The resulting solution is held at 0 C. for about 14 hours and thenpoured onto an excess of crushed ice. The solution is adjusted to pH 6with saturated potassium bicarbonate solution. The solid material isremoved by filtration and washed with ice- Water. The solid is extractedwith about 10 ml. of ethyl acetate and the ethyl acetate solution driedover sodium sulfate and then concentrated essentially to dryness. Asmall volume of hexane is added to the residue and the solidl-methyl-5-nitro-2-imidazolymethyl thiolcarbamate removed by filtration.There are obtained in this Way 4.34 g of1-methyl-5-nitroimidazol-2-ylmethyl thiolcarbamate; M.P. 138-140 C.

EXAMPLE 5 1-methyl-5-nitroimidazol-2-ylmethyl carbamatel-methyl-5-nitroimidazol-2-ylmethyl chloroformate as obtained inaccordance with Example 1 is cooled to 0 C. and 25 ml. of liquid ammoniaadded thereto. The resulting mixture is stirred for 10 minutes in thecold and then an additional 25 ml. of liquid ammonia is added. Themixture is then allowed to warm to room temperature and stirred untilthe excess ammonia evaporates. The residue thus obtained is dissolved in100 ml. of water and the aqueous solution extracted with three 100 ml.portions of ethyl acetate. The ethyl acetate extracts are combined,backwashed with 25 ml. of Water and then dried over sodium sulfate. Theethyl acetate is then concentrated to thionformate,1-methyl-5-nitroimidazol-2-ylmethyl chlorodithioformate in place ofl-methyl-5-nitroimidazol-2-ylmethyl chloroformate, there is obtained thecorresponding l-methyl-S-nitroimidazol-Z-ylmethyl thiocarbamate,1-methyl-5-nitroimidazol-2-ylmethyl thioncarbamate, and1-methyl-5-nitroimidazol-2-ylmethyl dithiocarbamate.

EXAMPLE 6 l-methyl-S-nitroimidazol-Z-ylmethyl carbamate 3.1 g., (0.02mole) of (1-methyl-2-hydroxymethyl)-5- nitroimidazole is dissolved in100 ml. of benzene and 25 ml. of pyridine. 1.9 g., (0.022 mole) ofgaseous carbamyl chloride is introduced into the stirred solution. Thesolution is allowed to stand at 15 C. for 8 hours and then concentratedunder reduced pressure. The residue is taken up in ethyl acetate, Washedwith ice-water, and the ethyl acetate extract dried over sodium sulfate.On evaporation of the solvent under reduced pressure, the residue isrecrystallized from acetone or ethyl acetate to yield 1-methyl-S-nitroimidazol-Z-ylmethyl carbamate; M.P. 166- 170 C.

In accordance with the above procedure but using dimethylcarbamylchloride or diethylcarbamyl chloride and adding these reagents in liquidrather than gaseous form to the reaction mixture in place of usingcarbamyl chloride. there is obtained the correspondingl-methyl-S-nitroimidazol-2-ylmethyl N,N-dimethylcarbamate andl-methyl-5-nitroimidazol-2-ylmethyl N,-N-diethylcarbamate.

In accordance with the above procedure but using thiocarbamyl chloride,dimethylthiocarbamyl chloride, and dimethylthiocarbamyl chloride, inplace of carbamyl chloride, there is obtained1-methyl-5-nitroimidazol-2-yl-rnethyl thioncarbamate,1-methyl-5-nitroimidazol-2-yl-methyl N,N-dimethylthioncarbamate, andl-methyl-S-nitroirnidazol-Z-ylmethyl N,N-diethylthioncarbamate.

EXAMPLE 7 l-methyl-S-nitroimidazol-Z-ylmethyl thiolcarbamate 3.5 g.,(.02 mole) of I-methyl-Z-mercapto methyl-5- nitroimidazole is dissolvedin 100 ml. of benzene and 25 ml. of pyridine under nitrogen. 1.9 g.,(0.022 mole) of gaseous carbamoyl chloride is introduced into thestirred solution. The solution is allowed to stand at 15 C. for 8 hoursand then concentrated under reduced pressure. The residue is taken up inethyl acetate, washed with icewater and the ethyl acetate extract driedover sodium sulfate. On evaporation of the solvent under reducedpressure, the residue is recrystallized from acetone or ethyl acetate toyield 1-methyl-5-nitroimidazol-2-ylmethyl thiolcarbamate; M.P. l38140 C.

In accordance with the above procedure but using dimethylcarbamoylchloride or diethylcarbamoyl chloride and adding these reagents inliquid rather than gaseous form to the reaction mixture in place ofcarbamoyl chloride, there is obtained the correspondingl-methyl-S-nitroimidazol-Z-ylmethyl N,N-dimethylthiolcarbamate and 1-methyl-S-nitroimidazol- 2 ylmethyl N,N-diethylthiolcarbamate.

In accordance with the above procedure but using thiocarbamoyl chlorideand dimethylthiocarbamoyl chloride and diethylcarbamoyl chloride, inplace of carbamoyl chloride, there is obtainedl-methyl-5-nitroimidazol-2-ylmethyl dithiocarbamate,1-methyl-5-nitroimidazol-2-ylmethyl N,N-dimethyldithiocarbamate, andl-methyl-S- nitroimidazol-2-ylmethy1 N,N-diethyldithiocarbamate.

EXAMPLE 8 1-methyl-S-nitroimidazol-Z-ylmethyl carbamate 1.57 g., (0.01mole) of 1-methyl-2-hydroxymethyl-5- nitroimidazole, 0.1 g. sodiumethoxide, 10 g. of ethyl carbamate, and 20 ml. of benzene are heatedunder reflux for 2 hours. The solvent is removed under reduced pressureand the residue stirred with 10 ml. of water. The mixture is extractedwith ethyl acetate. The ethyl acetate fraction in dried over sodiumsulfate and evaporated to give crude 1-methyl-5-nitroimidazol-2-ylmethylcarbamate.

In accordance with the above procedure but starting withl-methyl-2-mercaptomethyl 5 nitroimidazole, in place ofl-methyl-Z-hydroxy methyl-S-nitroimidazole and using ethyl carbamate,there is obtained the corresponding 1-methyl-S-nitroimidazol-Z-ylmethylthiolcarbamate.

EXAMPLE 9 l-methyl-5-nitroimidazol-2-ylmethyl methylcarbamate 6 g. of1-methyl-2-hydroxymethyl-5-nitroimidazole and 3.5 ml. of methylisocyanate are added to 200 ml. of benzene containing 0.5 ml. ofpyridine. The resulting mixture is refluxed until complete solution isobtained. The solvent is then removed by evaporation under reducedpressure. The partially crystalline material thus obtained isrecrystallized from 12 ml. of water to give 1.14 g. of1-methyl-5-nitroimidazol 2 ylmethyl methylcarbamate; M.P. 99l01 C.

In accordance with the above procedure, but starting withl-methyl-Z-mercaptomethyl 5 nitroimidazole, in place of1-methyl-2-hydroxymethyl 5 nitroimidazole, there is obtained thecorresponding l-methyl-S-nitrOimidazol-2-ylmethyl thiolmethylcarbamate.

EXAMPLE 10 1-methyl-5-nitroimidazol-2-ylmethyl methylthioncarbamate 0.5g. of 1-methyl-2-hydroxymethyl-S-nitroimidazole and 0.28 g. of methylisothiocyanate are added to 20 ml. of benzene containing 0.54 ml. oftriethylamine. The resulting mixture is refluxed for 23 hours. It isthen concentrated almost to dryness in vacuo and the solid materialremoved by filtration. This product is l-methyl-S- nitroimidazol 2ylmethyl methylthioncarbamate; M.P. 133.5l35 C. It is recrystallizedfrom water to give substantially pure material; M.P. l35.5136 C.

In accordance with the above procedure, but starting withl-methyl-Z-mercaptomethyl 5 nitroimidazole, in place of1-methyl-2-hydroxymethyl 5 nitroimidazole, there is obtained thecorresponding l-methyl-S-nitroimidazol-Z-ylmethyl dithiocarbamate.

EXAMPLE 11 1-n-butyl-5-nitroimidazol-2-ylmethyl carbamate A mixture of16.9 g. (0.1 mole) of 1-n-butyl-5-nitroimidazole, 15 g. (0.5 mole) ofparaformaldehyde and 150 ml. of dimethylsulfoxide is heated in a sealedtube overnight at 110l50 C. The dimethylsulfoxide is removed completelyat reduced pressure, and the residue is dissolved in water and extractedwith chloroform. The chloroform extract is dried and concentrated. Theresidue is dissolved in ethyl acetate, and the solution is charged on acolumn of alumina. Elution with ethyl acetate and evaporation of thesolvent yields 1-n-butyl-2-hydroxymethyI-S-nitroimidazole.

A solution of 2.0 g. (0.01 mole) ofl-n-butyl-2-hydroxymethyl-S-nitroimidazole in 25 ml. of dry pyridine isstirred at 0 C. and 1.85 g. (0.012 mole) of phenyl chloroformate isslowly added. The reaction mixture is stirred for 3-4 hours at roomtemperature and is poured into about 200 ml. of water. The mixture iscooled overnight and the precipitate of l-n-butyl-5-nitroimidazol-2-ylmethyl phenyl carbonate is separated by filtration.

A solution of 640 mg. (0.002 mole) of l-n-butyl-S-nitroimidazol-Z-ylmethyl phenyl carbonate in 10 ml. of chloroform,cooled in an ice-bath, is saturated with dry ammonia. The mixture isallowed to stand for 1 day at 5 C. 1-n-butyl-5-nitroimidazol-2-ylmethylcarbamate is obtained after evaporating the solvent and washing theresidue with water.

In accordance with the above procedure, but starting withl-methyl-S-nitroimidazole, l-ethyl-S-nitroimidazole and1-propyl-5-nitroimidazole, in place of l-n-butyl-S- nitroimidazole,there is obtained the corresponding 1- methyl-S-nitroimidazol-Z-ylmethylcarbamate, l-ethyl-S- nitroimidazol-Z-ylmethyl carbamate, and1-propyl-5-nitro imidazol-Z-ylmethyl carbamate.

EXAMPLE 12 1-(2'-acetoxyethyl)-5-nitroimidazol-2-ylmethyl carbamate and1-(2-hydroxyethyl)-S-nitroimidazol-Z-ylmetliyl carbamate on a column ofalumina. Elution with ethyl acetate and evaporation of the solventyields 1-(2-acetoxyethyl)-2- hydroxymethyl-S-nitroimidazole; M.P.138-145 C.

A solution of 1.4 g. of1-(2'-acetoxyethyl)-2-hydroxymethyl-S-m'troimidazole in 25 ml. of drypyridine is stirred at C. and 1.85 g. (0.012 mole) of phenylchloroformate is slowly added. The reaction mixture is stirred for 3-4hours at room temperature and is poured into about 200 ml. of water. Themixture is cooled overnight and the precipitate of1-(2acetoxyethyl)-5-nitroimidazol- 2-ylmethyl phenyl carbonate, M.P.9395 C., is separated by filtration.

1.5 g. of 1-(2'acetoxyethyl)-S-nitroimidazol-Z-ylmethyl phenyl carbonateis dissolved slowly in 50 ml. of liquid ammonia. After solution iscomplete, the ammonia is permitted to evaporate and the residue washedwith ethanol and recrystallized to yield1-(2'-acetoxyethyl)-5-nitroimidazol-2-ylmethyl carbamate; M.P. 160-162C.

6 g. of 1-(2'-acetoxyethyl)-5-nitroimidazol-2-ylmethyl carbamate isdissolved in 100 ml. of ethanol and the solution saturated with ammonia.The mixture is allowed to stand for 12 hours at 15 C. and the solventremoved by evaporation under reduced pressure. The residue is washedwith methanol to yield l-(2'-hydroxyethyl)-5-nitroimidazol-2-ylmethylcarbamate; M.P. 150152 C.

EXAMPLE 13 1-(2-hydroxypropyl)-5-nitroimidazol-2-ylmethyl carbamate Amixture of 21.3 g. (0.1 mole) of 1-(2-acetoxypropyl)--nitroimidazole, 15g. (0.5 mole) of paraformaldehyde and 150 ml. of dimethylsulfoxide isheated in a sealed tube overnight at 110-150 C. The dimethylsulfoxide isremoved completely at reduced pressure, and the residue is dissolved inwater and extracted with chloroform. The chloroform extract is dried andconcentrated. The residue is dissolved in ethyl acetate, and thesolution is charged on a column of alumina. Elution with ethyl acetateand evaporation of the solvent yield 1-(2'- acetoxypropyl) 2hydroxymethyl 5 nitroimidazole; M.P. 150-155 C.

A solution of 2.43 g. (0.01 mole) of1-(2'-acetoxypropyl)-2-hydroxymethyl-S-nitroimidazole in 25 ml. of drypyridine is stirred at 0 C. and 1.85 g. (0.012 mole) of phenylchloroformate is slowly added. The reaction mixture is stirred for 3-4hours at room temperature and is poured into about 200 ml. of water. Themixture is cooled overnight and the precipitate of1-(2'acetoxypropyl)-S-nitroimidazol-2-ylmethyl phenyl carbamate isseparated by filtration.

A solution of 726 mg. (0.002 mole) of1-(2-acetoxypropyl)-5-nitroimidazol-2-ylmethyl phenyl carbamate in 10ml. of chloroform, cooled in an ice-bath, is saturated with dry ammonia.It is allowed to stand for 5 days at 5 C. 1-(2'acetoxypropyl)-5nitroimidazol 2-ylmethyl carbamate is obtained crystalline, M.P. 106-108C.,

after evaporating the solvent and washing the residue with water.

The 1-(2-acetoxypropyl)-5-nitroimidazol 2-ylmethyl carbamate produced asabove is redissolved in methanol and the solution saturated withanhydrous ammonia. The T mixture is allowed to stand for 2 days at 15 C.and concentrated under reduced pressure. The residue is recrystallizedfrom ethyl acetate, ethyl alcohol or a mixture of the two, to yield1-(2-hydroxypropyl)-5-nitroimidazol-2-ylmethyl carbamate.

In accordance with the above procedure, but starting with1-(2'-acetoxybutyl)-5-nitroimidazole,1-(2'acetoxypentyl)-5-nitroimidazole, 1-(3'-acetoxybutyl) 5nitroimidazole, 1-(3'-acetoxypentyl)-5 nitroimidazole and1-(3-acetoxypropyl)-5 nitroimidazole, in place of 1-(2- acetoxypropyl) 5nitroimidazole, there is obtained the corresponding1-(2'-hydroxybutyl)-5-nitroimidazol 2 ylmethyl carbamate,1-(2-hydroxypentyl) S-nitroimidazol-2-2ylmethyl carbamate,1-(3'-hydroxybutyl)-5-nitroimidazol-Z-ylmethyl carbamate, 1-(3-hydroxypentyl)-5- nitroimidazol-Z-ylmethyl carbamate and 1-(3-hydroxypropyl)-5-nitroimidazol-2-yl-methyl carbamate, and thecorresponding 1 (acetoxyalkyl) 5 nitroimidazol 2 ylmethyl carbamateanalogs thereof.

In accordance with the above procedure, but using the propionoxy,'butyroxy or valeroxy analogs of any of the aforementioned1-hydroxyalkyl-S-nitroimidazoles as starting materials in place of the1-acetoxyalkyl-5-nitroimidazoles utilized above, there are obtained thecorresponding 1-alkanoyloxyalkyl-S-nitroimidazol-2-ylmethyl carbamatesand l-hydroxyalkyl 5 nitroimidazol 2 ylmethyl carbamates.

EXAMPLE 14 1-( 1-methyl-5 -nitroimidazol-2-yl )ethyl carbamate Asolution of 0.01 moles of 1-methyl-2-(1-hydroxyethyl)-5-nitroimidazolein 25 ml. of dry pyridine is stirred at 0 C. and 1.85 g. (0.012 mole) ofphenyl chloroformate is slowly added. The reaction mixture is stirredfor 3- 4 hours at room temperature and is poured into about 200 ml. ofwater. The mixture is cooled overnight and the precipitate of1-(1-methyl-5-nitroimidazol-2'-yl) ethyl phenyl carbonate is separatedby filtration.

A solution of 0.005 mole of 1-(1'-methyl-5'-nitroimidazol-2-yl)ethylphenyl carbonate in 10 ml. of chloroform is cooled in an ice-bath, andis saturated with dry ammonia. It is allowed to stand for 5 days at 5 C.1-(1-methyl 5-nitroimidazol 2'-yl) ethyl carbamate, M.P. 156.5-" C., isobtained as a crystalline precipitate.

EXAMPLE l5 2- 1'-methy1-5'-nitroimidazol-2'-yl) ethyl carbamate Asolution of 0.01 mole of 1-methyl-2-hydroxyethyl-5- nitroimidazole in 25ml. of dry pyridine is stirred at 0 C..and 1.85 g. (0.012 mole) ofphenyl chloroformate is slowly added. The reaction mixture is stirredfor 3-4 hours at room temperature and is poured into about 200 ml. ofwater. The mixture is cooled overnight and the precipitate of2-(1-metl1yl 5 nitroimidazol-2-yl)ethyl phenyl carbonate is separated byfiltration.

A solution of 0.005 mole of 2-(1'-methyl-5-nitroimidazol-2'-yl) ethylphenyl carbonate in 10 ml. of chloroform is cooled in an ice-bath, andis saturated with dry ammonia. It is allowed to stand for 5 days at 5 C.2-(1'- methyl-5-nitroimidazol-2-yl)ethyl carbamate is obtained as acrystalline precipitate; M.P. -166" C.

EXAMPLE 16 1-methyl-S-nitroimidazol-Z-ylmethyl hydroxymethylcarbamate Amixture of 2.0 g. (0.01 mole)l-methyl-S-nitroimidazol-2-yl-methylcarbate, 0.6 g. (0.02 mole) ofparaformaldehyde and 6 ml. of dimethyl sulfoxide is heated at 100 C. ina sealed tube for 24 hours. Evaporation of the solvent leaves a viscousresidue which is dissolved in 3 ml. of dimethyl formamide. After theaddition of 5 ml.

13 of water and standing for 24 hours, a crystalline precipitate isobtained which is separated by filtration, air dried, andrecrystallization from ethyl acetate to yield l-methyl--nitroimidazol 2ylmethyl N-hydroxymethylcarbamate.

EXAMPLE 17 1-methyl-5-nitroimidazol-2-ylmethy1 N-2- hydroxyethylcarbamate 1.22 g. of ethanolamine is added at 15 C. to a solutionof 2.93 g. of 1 methyl-5-nitroimidazol-Z-ylmethyl phenylcarbonate in ml.of chloroform. The mixture is stirred for 7 hours and at the end of thistime, the solid product is removed by filtration. Recrystallized fromethyl acetate gives 1-methyl-5-nitroimidazol-2-ylmethylN-2'-hydroxyethyl carbamate; M.P. 132-135 C.

In accordance with the above procedure, but starting with propanolamine,butanolamine, in place of ethanolamine, there is obtained thecorresponding 1-methyl-5- nitroimidazol-Z-ylmethylN-3-hydroxypropylcarbamate, and l-methyl-5-nitroimidazol-2-ylmethylN-hydroxybutylcarbamate.

EXAMPLE 18 1-methyl-5-nitroirnidazol-2-ylmethyl ethoxymethylcarbamate Amixture of 1.15 g. (.005 mole) of l-methyl-S-nitroimidazol-Z-ylmethylhydroxymethylcarbamate, .05 g. of p-toluenesulfonic acid and 20 ml. ofethanol is allowed to stir overnight at room temperature. Afterevaporation, the residue is dissolved in 50 ml. of chloroform and thechloroform solution washed with dilute sodium bicarbonate solution. Thechloroform solution, after drying over sodium sulfate, is evaporated todryness. The residue is recrystallized from ethyl acetate to yield1-methyl-5-nitroimidazol-Z-ylmethyl N-ethoxymethylcarbamate.

In accordance with the above procedure, but using npropanol, n-butanolor n-pentanol in place of ethanol, there is obtained the correspondingl-methyl-S-nitroimidazol-2-ylmethyl N-propoxymethylcarbate, 1 methyl-5-nitroimidazol-Z-ylmethyl N-butoxymethylcarbamate, andl-methyl-S-nitroimidazol 2 ylmethyl N-pentoxymethylcarbamate.

EXAMPLE 19 1-methyl-5-nitroimidazol-2-ylmethyl N-ethoxyethylcarbamate1.78 g., (0.02 mole) of 2-ethoxyeth'ylamine is added at C. to a solutionof 2.93 g. of l-methyl-S-nitroimidazol-2-ylmethylphenylcarbonate in 10ml. of chloroform. The mixture is stirred for 7 hours and at the end ofthis time, the solution is evaporated to dryness. The residue isslurried with water and the solid product after filtration, isrecrystallized from ethanol-water to give 1-methy1-5-nitroimidazol-Z-ylmethyl N-ethoxyethylcarbamate.

In accordance with the above procedure, but starting with3-ethoxypropylamine, 4ethoxybutylamine, S-ethoxypentylamine, andfi-ethoxyhexylamine, in place of 2-ethoxyethylamine, there is obtainedthe corresponding 1- methyl-S-nitroimidazol-Z-ylmethylN-3-ethoxypropylcarbamate, l-methyl-S-nitroimidazol-2-ylmethylN-4-ethoxybutylcarbamate, 1 methyl-5-nitroimidazol-2-ylmethyl N-5-ethoxypentylcarbamate, and 1 methyl-S-nitroimidazol- Z-ylmethylN-6-ethoxyhexylcarbamate.

EXAMPLE l-methyl-S-nitroimidazol-2-ylmethyl N-mercaptoethylcarbamate1.54 g., (0.02 mole) of 3-mercaptoethylamine is added at 15 C. to asolution of 2.77 g. of l-methyl-S-nitroimidazol-2-ylmethylphenylcarbonate in 10 ml. of chloroform. The mixture is stirred for 7hours and at the end of this time, the solid product is removed byfiltration. Recrystallization from ethanol gives1-methyl-5-nitroimidazol-2- ylmethyl N-2'-mercaptoethylcarbamate.

14 In accordance with the above procedure, but starting with3-mercaptopropylamine and 4-mercaptobutylamine, in place ofZ-mercaptoethylamine, there is obtained the correspondingl-methyl-5-nitroimidazol-2-ylmethyl N-3'- mercaptopropylcarbamate and 1methyl-S-nitroimidazol- 2-ylmethy1 N- '-mercaptobutylcarbamate.

EXAMPLE 21 1-methyl-S-nitroimidazol-2-ylmethyl N-ethylthioethylcarbamate2.12 g., (0.02 mole) of ethylthioethylamine is added at 15 C. to asolution of 2.77 g. of l-methyl-S-nitro-imidazole-2-ylmethylphenylcarbonate in 10 m1. of chloroform. The mixture is stirred for 7hours and then evaporated to dryness. The residue is triturated withether and the solid product is removed by filtration. Recrystallizationfrom ethanol gives 1-methyl-5-nitroimidazol-2-ylmethyl N-2-ethylthioethylcarbamate.

In accordance with the above procedure, but starting with2-methylthioethylamine, 2-propylthioethylamine, 2- butylthioethylamine,or Z-benzylthioethylamine, in place of Z-ethylthioethylamine, there isobtained the corresponding 1-methyl-S-nitroimidazol-Z-ylmethyl N--methylthioethylcarbamate, l-methyl-5-nitroimidazol-2-ylmethy1 N-2'-propylthioethylcarbamate, l-methyl-5-nitroimidazo1-2- ylmethylN-2'-butylthioethylcarbamate, and l-methyl-S- nitroimidazol-Z-ylmethylN-2'-benzylthioethylcarbamate.

EXAMPLE 22 l-methyl-S-nitroimidazol-Z-ylmethyl N-hydroxycarbamate 0.386g. of sodium is dissolved in 40 m1. of methanol and the solution cooledin an ice bath. 1.17 g. of hydroxylamine hydrochloride is added to thecold methanol solution. To the resulting mixture there is added over aperiod of 45 minutes 2.33 g. of l-methyl-S-nitroimidazol-Z-ylmethylphenyl carbonate in 60 ml. of methanol. The resulting mixture is heldfor 15 hours at refrigerator temperature and at the end of this time,the solid material present is removed by filtration. The solid is washedwith alcohol and then with hexane, and dried to give l-methyl-5-nitroimidazol-2-ylmethyl N-hydroxycarbamate; M.P. 189190 C.

In accordance with the above procedure, but starting withN-methylhydroxylamine hydrochloride, N-propylhydroxylaminehydrochloride, N-phenylhydroxylamine hydrochloride, andN-benzylhydroxylamine hydrochloride, in place of hydroxylamine, there isobtained the corresponding 1-methyl-5-nitroimidazol-Z-ylmethyl N-methyl-N-hydroxycarbamate, 1-methyl-S-nitroimidazol-Z-ylmethylN-propyl-N-hydroxycarbamate, l-methyl-S-nitroimidazol-2-ylmethylN-phenyl-N-hydroxycarbamate, and 1- methyl-S-nitroimidazol-2-ylmethylN-benzyl-N-hydroxycarbamate.

EXAMPLE 23 1- 2-acetoxyethyl) -S-nitroimidazol-Z-ylmethyl N-hydroxycarbamate 3.66 g. of l-(2'-acetoxyethyl)-5-nitroimidazol-2-ylmethylphenyl carbonate is dissolved in 20 ml. of methanol and treated withfreshly prepared hydroxylamine from .72 g. of hydroxylaminehydrochloride and .6 g. of sodium methoxide in 20 ml. of methanol. Theresidue is recrystallized from ethanol to yieldl-(2-acetoxyethyl)-5-nitroimidazol- 2-ylmethyl N-hydroxycarbamate; M.P.153-155 C.

EXAMPLE 24 1-methyl-5-nitroimidazol-2-ylmethyl .N-hydroxythioncarbamate0.56 g. (0.005 mole) of potassium t-butoxide is dissolved in 20 ml. ofethanol and 0.35 g. (0.005 mole) of hydroxylamine hydrochloride is addedand the mixture stirred for 5 minutes. 0.732 g. (0.0025 mole) ofl-methyl- 5-nitroimidazol-2-ylmethyl phenyl thioncarbonate is added andthe mixture allowed to stand for 1 hour. The solvent is removed underreduced pressure, and water added to the residue to yield1-methyl-5-nitroimidazol-2-ylmethyl N-hydroxythioncarbamate; M.P. 9495C. (dec.).

In accordance with the above procedure, but starting withN-methylhydroxylamine, N-propylhydroxylamine, N- phenylhydroxylamine,and N-benzylhydroxylamine, in place of hydroxylamine, there is obtainedthe corresponding 1-methyl-S-nitroimidazol-2-ylrnethylN-methyl-N-hydroxythioncarbamate, 1-methyl-S-nitroimidazol-Z-ylmethylN-propyl-N-hydroxythioncarbamate, and l-rnethyl-S-nitroimidazol-Z-ylmethyl N-benzyl-N-hydroxythioncarbamate.

PREPARATION 1 1-methyl-5-nitroimidazol-2-ylmethyl phenyl carbonate 15.9ml. dry pyridine and 4.87 g. (0.031 mole) of 1-methyl-2-hydroxymethyl-5-nitroimidazole are added to a flask fitted witha stirrer, thermometer and addition funnel. The mixture is stirred atroom temperature until the solid dissolves and then cooled to C. 5.05 g.(0.0322 mole) of phenylchloroformate is added to the stirred solutionover an 80 minute period, while maintaining the temperature at -10 C.with external cooling. On completion of the addition the reactionmixture is stirred at about 25 C. for 2 /2 hours. It is then poured into60 ml. of icewater with good agitation. The resulting slurry is stirredfor 40 minutes and the resulting solidl-methyl-S-nitroimidazol-Z-ylmethyl phenyl carbonate collected byfiltration. The solid is washed thoroughly with water and dried in vacuoat 50 C. A yield of 8.24 g. is obtained; M.P. 92 95 C. Recrystallizationfrom 1:3 methanol-hexane gives pure product; M.P. 100-100.5 C. Inaccordance with the above procedure, but starting with1-methyl-2-mercaptomethyl 5 nitroimida'zole, in place ofl-methyl-Z-hydroxymethyl 5 nitroimidazole, there is obtained thecorresponding 1-rnethyl-5-nitroimidazol-2-yl-methyl phenylthiocarbamate.

In accordance with the above procedure, but starting with1-methyl-2-(1-hydroxyethyl)-5-nitroimidazole, 1-methyl-2-(2-hydroxyethyl) 5 nitroimidazole and 3-(1-methyl-5-nitroimidazo1e-2-yl)prop-2-en-1-ol in place of 1-methyl-2*hydroxymethyl-5-nitroimidazole, there is obtained thecorresponding 1-(1-methy1-5-nitroirnidazol-2- yl)-ethyl-phenylcarbonate, 2-(1-methyl-S-nitroimidazol-Z- yl)-ethyl-phenyl carbonate,and 3-(l-methyl-5-nitroimidazol-2-yl)-prop-2-en-l-yl phenyl carbonate.

PREPARATION 2 1-methyl-5-nitroimidazol-Z-ylmethylphenyl thionocarbonate5.17 g. phenoxythiocarbonyl chloride is added dropwise to a coldsolution of 4.71 g. of l-methyl-2-hydroxymethyl-S-nitroimidazole in 15ml. of pyridine. During addition the pyridine solution is cooled in anice bath. After about one-third of the carbonyl chloride is added, ml.of pyridine is added to the reaction mixture. On completion of theaddition, the mixture is allowed to 98 C. On further recrystallizationfrom benzene-hexene the product melts at 103-105 .5 C.

In accordance with the above procedure, but starting withl-methyl-2-mercaptomethyl-5-nitroimidazole in place of1-methyl-2-hydroxymethyl-5-nitroimidazole, there is obtained thecorresponding 1-methy1-6-nitroimidazole-2- yl-methyl phenyldithiocarbonate.

We claim:

1. A compound of the formula -N l l OrN Q-A-G-N wherein R is loweralkylof 1-5 carbon atoms, Q is loweralkylene or loweralkylidene of 1-4 carbonatoms, A and M are each oxygen or sulfur, R is hydrogen or loweralkyl ofl-3 carbon atoms, and R is hydroxy, (hydroxy) loweralkyl, (loweralkoxy)loweralkyl, (thiol)1oweralkyl or (loweralkylthio)loweralkyl, theloweralkyl in R being from 1 to 4 carbon atoms.

2. A compound of claim 1 in which R is methyl.

3. A compound of claim 2 in which Q is methylene.

4. A compound of claim 3 in which both A and M are oxygen.

5. A compound of claim 4 in which R is hydrogen.

6. The compound of claim 5 in which R is hydroxy.

7. The compound of claim 5 in which R, is 2'-(hydroxy) ethyl.

8. The compound of claim 5 in which R; is hydroxy methyl.

9. A compound of claim 2 in which Q is l-ethylidene.

10. A compound of claim 9 in which both A and M are oxygen.

11. A compound of claim 10 in which R is hydrogen.

12. A compound of claim 2 in which Q is ethylene.

13. A compound of claim 12 in which both A and M are oxygen.

14. A compound of claim 13 in which R is hydrogen.

References Cited UNITED STATES PATENTS 3,299,090 1/1967 Hoff et al.260-309 3,325,507 6/1967 Kollonitsch 260-309 3,378,552 4/1968 Henry260-309 FOREIGN PATENTS 683,796 1/ 1967 Belgium 260 309 NATALIE TROUSOF,Primary Examiner

